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Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance.

ABSTRACT: A 50-fold variation in mRNA and protein levels of the mesoderm-specific transcript gene (Mest) in white fat of C57BL/6J (B6) mice fed an obesogenic diet is positively correlated with expansion of fat mass. MEST protein was detected only in adipocytes, in which its induction occurred with both unsaturated and saturated dietary fat. To test the hypothesis that MEST modulates fat mass expansion, its expression was compared to that of stearoyl CoA desaturase (Scd1) in B6 mice exposed to diets and environmental temperatures that generated conditions separating the effects of food intake and adiposity. Under a range of conditions, Mest expression was always associated with variations in adiposity, whereas Scd1 expression was associated with the amount of saturated fat in the diet. Mest mRNA was expressed at its highest levels during early postnatal growth at the onset of the most rapid phase of fat mass expansion. MEST is localized to the endoplasmic reticulum/Golgi apparatus where its putative enzymatic properties as a lipase or acyltransferase, predicted from sequence homology with members of the alpha/beta fold hydrolase superfamily, can enable it to function in lipid accumulation under conditions of positive energy balance. Variations in adiposity and Mest expression in genetically identical mice also provides a model of epigenetic regulation.

SUBMITTER: Nikonova L

PROVIDER: S-EPMC2574032 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance.

Nikonova Larissa L Koza Robert A RA Mendoza Tamra T Chao Pei-Min PM Curley James P JP Kozak Leslie P LP

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20080721 11

A 50-fold variation in mRNA and protein levels of the mesoderm-specific transcript gene (Mest) in white fat of C57BL/6J (B6) mice fed an obesogenic diet is positively correlated with expansion of fat mass. MEST protein was detected only in adipocytes, in which its induction occurred with both unsaturated and saturated dietary fat. To test the hypothesis that MEST modulates fat mass expansion, its expression was compared to that of stearoyl CoA desaturase (Scd1) in B6 mice exposed to diets and en ...[more]

PMID: 18644838

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Project description:Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript (Mest), a paternally-expressed imprinted gene belonging to the α/β-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated with adipose tissue expansion (ATE). To elucidate a role for MEST in ATE, mice were developed with global and adipose tissue inactivation of Mest. Mice with homozygous (MestgKO) and paternal allelic (MestpKO) inactivation of Mest were born at expected Mendelian frequencies, showed no behavioral or physical abnormalities, and did not perturb expression of the Mest locus-derived microRNA miR-335. MestpKO mice fed HFD showed reduced ATE and adipocyte hypertrophy, improved glucose tolerance, and reduced WAT expression of genes associated with hypoxia and inflammation compared to littermate controls. Remarkably, caloric intake and energy expenditure were unchanged between genotypes. Mice with adipose tissue inactivation of Mest were phenotypically similar to MestpKO, supporting a role for WAT MEST in ATE. Global profiling of WAT gene expression of HFD-fed control and MestpKO mice detected few differences between genotypes; nevertheless, genes with reduced expression in MestpKO mice were associated with immune processes and consistent with improved glucose homeostasis. Ear-derived mesenchymal stem cells (EMSC) from MestgKO mice showed no differences in adipogenic differentiation compared to control cells unless challenged by shRNA knockdown of Gpat4, an enzyme that mediates lipid accumulation in adipocytes. Reduced adipogenic capacity of EMSC from MestgKO after Gpat4 knockdown suggests that MEST facilitates lipid accumulation in adipocytes. Our data suggests that reduced diet-induced ATE in MEST-deficient mice diminishes hypoxia and inflammation in WAT leading to improved glucose tolerance and insulin sensitivity. Since inactivation of Mest in mice has minimal additional effects aside from reduction of ATE, an intervention that mitigates MEST function in adipocytes is a plausible strategy to obviate obesity and type-2-diabetes.

Project description:BackgroundA growing body of evidence suggests that many downstream pathologies of obesity are amplified or even initiated by molecular changes within the white adipose tissue (WAT). Such changes are the result of an excessive expansion of individual white adipocytes and could potentially be ameliorated via an increase in de novo adipocyte recruitment (adipogenesis). Mesoderm-specific transcript (MEST) is a protein with a putative yet unidentified enzymatic function and has previously been shown to correlate with adiposity and adipocyte size in mouse.ObjectivesThis study analysed WAT samples and employed a cell model of adipogenesis to characterise MEST expression and function in human.Methods and resultsMEST mRNA and protein levels increased during adipocyte differentiation of human multipotent adipose-derived stem cells. Further, obese individuals displayed significantly higher MEST levels in WAT compared with normal-weight subjects, and MEST was significantly correlated with adipocyte volume. In striking contrast to previous mouse studies, knockdown of MEST enhanced human adipocyte differentiation, most likely via a significant promotion of peroxisome proliferator-activated receptor signalling, glycolysis and fatty acid biosynthesis pathways at early stages. Correspondingly, overexpression of MEST impaired adipogenesis. We further found that silencing of MEST fully substitutes for the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) as an inducer of adipogenesis. Accordingly, phosphorylation of the pro-adipogenic transcription factors cyclic AMP responsive element binding protein (CREB) and activating transcription factor 1 (ATF1) were highly increased on MEST knockdown.ConclusionsAlthough we found a similar association between MEST and adiposity as previously described for mouse, our functional analyses suggest that MEST acts as an inhibitor of human adipogenesis, contrary to previous murine studies. We have further established a novel link between MEST and CREB/ATF1 that could be of general relevance in regulation of metabolism, in particular obesity-associated diseases.

Project description:BackgroundAddition of capsaicin (CAPS) to the diet has been shown to increase energy expenditure; therefore capsaicin is an interesting target for anti-obesity therapy.AimWe investigated the 24 h effects of CAPS on energy expenditure, substrate oxidation and blood pressure during 25% negative energy balance.MethodsSubjects underwent four 36 h sessions in a respiration chamber for measurements of energy expenditure, substrate oxidation and blood pressure. They received 100% or 75% of their daily energy requirements in the conditions '100%CAPS', '100%Control', '75%CAPS' and '75%Control'. CAPS was given at a dose of 2.56 mg (1.03 g of red chili pepper, 39,050 Scoville heat units (SHU)) with every meal.ResultsAn induced negative energy balance of 25% was effectively a 20.5% negative energy balance due to adapting mechanisms. Diet-induced thermogenesis (DIT) and resting energy expenditure (REE) at 75%CAPS did not differ from DIT and REE at 100%Control, while at 75%Control these tended to be or were lower than at 100%Control (p = 0.05 and p = 0.02 respectively). Sleeping metabolic rate (SMR) at 75%CAPS did not differ from SMR at 100%CAPS, while SMR at 75%Control was lower than at 100%CAPS (p = 0.04). Fat oxidation at 75%CAPS was higher than at 100%Control (p = 0.03), while with 75%Control it did not differ from 100%Control. Respiratory quotient (RQ) was more decreased at 75%CAPS (p = 0.04) than at 75%Control (p = 0.05) when compared with 100%Control. Blood pressure did not differ between the four conditions.ConclusionIn an effectively 20.5% negative energy balance, consumption of 2.56 mg capsaicin per meal supports negative energy balance by counteracting the unfavorable negative energy balance effect of decrease in components of energy expenditure. Moreover, consumption of 2.56 mg capsaicin per meal promotes fat oxidation in negative energy balance and does not increase blood pressure significantly.Trial registrationNederlands Trial Register; registration number NTR2944.

Project description:BackgroundThe practical relevance of metabolic adaptation remains a controversial issue. To the best of our knowledge, no study has properly evaluated the role of metabolic adaptation in modulating weight loss outcomes. Therefore, the aim of this study was to determine the association between metabolic adaptation, at the level of resting metabolic rate (RMR), and weight and fat mass (FM) loss after low-energy diets (LED), after adjusting for dietary adherence and other confounders.Methods71 individuals with obesity (BMI: 34.6 ± 3.4 kg/m2; age: 45.4 ± 8.2 years; 33 males) were randomized to one of three 1000 kcal/day diets for 8 weeks. Body weight, FM and fat-free mass (FFM) (air displacement plethysmography), RMR (indirect calorimetry) and physical activity level (PAL) (armbands) were measured at baseline and at week 9. Metabolic adaptation at week 9 was defined as measured RMR minus predicted RMR at week 9. An equation to predict RMR was derived from baseline data of all participants that were part of this analysis and included age, sex, FM and FFM as predictors. Dietary adherence was calculated from RMR, PAL and body composition changes. Linear regression was used to assess the potential role of metabolic adaptation in predicting weight and FM loss after adjusting for dietary adherence, average PAL, sex, baseline FM and FFM and randomization group.ResultsParticipants lost on average 14 ± 4 kg of body weight (13 ± 3%) and presented with metabolic adaptation (-92 ± 110 kcal/day, P < 0.001). Metabolic adaptation was a significant predictor of both weight (β = -0.009, P < 0.001) and FM loss (β = -0.008, P < 0.001), even after adjusting for confounders (R2 = 0.88, 0.93, respectively, P < 0.001 for both). On average, an increase in metabolic adaptation of 50 kcal/day was associated with a 0.5 kg lower weight and FM loss in response to the LED.ConclusionIn individuals with obesity, metabolic adaptation at the level of RMR is associated with less weight and FM loss in response to LED. Trial registration ID: NCT02944253.

Dataset Information

Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance.

Publications

Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance.

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